extremely grateful to the Burroughs Wellcome Co. and to Hoffmann-La Roche Inc. for their support of my research in Tuckahoe from 1960 to 1970 and in Nutley from 1970 to the present. Looking back at the names of earlier recipients of the Clowes Award, I realize that I am the 6th Clowes Lecturer who, at one time or another in his career, has been associated with the McArdle Laboratory for Cancer Research at the University of Wisconsin. I believe that the large number of awardees associated with McArdle is telling us something about the genius of Dr. Harold Rusch who established McArdle with a handful of outstanding young investigators. Dr. Rusch helped to develop in his associates an intense devotion to fundamental cancer research, and he provided his colleagues with an at mosphere that encouraged them to have critical but construc tive interactions with each other in ways that stimulated excel lence in research by all of the members of the group. In 1952, I had the good fortune of coming to McArdle as a graduate student of Drs. James and Elizabeth Miller. Although I failed in my first research assignment, which was to synthesize pure 2amino-1-naphthol, the Millers had great patience with me, and they tried very hard to instill their high standards into my research. Whatever small accomplishments I may have made to biomÃ©dical research were in large part the result of the excellent training and encouragement that I received from Jim and Betty Miller. An important problem that has been of great interest to me for many years is individuality in the response of human beings and other living organisms to foreign chemicals. Why does a drug or an environmental pollutant cause toxicity in one person and not in another person? Why do some cigarette smokers develop lung cancer whereas other cigarette smokers do not? One of the causes of variability in the response of human beings to a foreign chemical is individuality in the rate of metabolism of the chemical. By the mid-1960s, it was recog nized by clinical pharmacologists that the plasma half-lives and steady state plasma concentrations of drugs varied by as much as 10to 20-fold among different individuals (42, 115, 204, 318). Because it seemed likely that there were also large differences in the metabolism of chemical carcinogens in dif ferent individuals, we investigated the metabolism of BP2 by

https://cancerres.aacrjournals.org/content/canres/42/12/4875.full.pdf

Induction of Microsomal Enzymes by Foreign Chemicals and Carcinogenesis by Polycyclic Aromatic Hydrocarbons: G. H. A. Clowes Memorial Lecture

Short-term tests for carcinogens and mutagens

This paper reviews the ability of a number of chemicals to induce sister-chromatid exchanges (SCEs). The SCE data for animal cells in vivo and in vitro, and human cells in vitro are presented in 6 tables according to their relative effectiveness. A seventh table summarizes what is known about the effects of specific chemicals on SCEs for humans exposed in vivo. The data support the concept that SCEs provide a useful indication of exposure, although the mechanism and biological significance of SCE formation still remain to be elucidated.

Sister-chromatid exchanges: a report of the GENE-TOX program.

The report reviews and evaluates the current literature (about 125 primary publications) on chemically induced specific locus mutations in the V79 Chinese hamster lung cell line. The V79 cell is convenient to use for mutagenesis studies since it has a rapid growth rate, high plating efficiency, and a stable karyotype. Mutation can be easily measured at either the hypoxanthine-guanine phosphoribosyl transferase or the Na+/K+ ATPase locus, both of which have been well characterized. Other less-studied markers are also described. We discuss the protocols for quantitative mutation studies including measurements of cytotoxicity, mutant expression times, mutant selection agents, cell densities during selection, and the stability and verification of mutant phenotypes. Mutations in the V79 cells by chemicals that require activation can be tested after their metabolism by cell homogenates or by intact cells, and the results with each type of activation are compared. For purposes of analysis, we classified a compound as mutagenic if it induced a mutation frequency that is at least 3 times higher than the spontaneous mutant frequency reported for that specific experiment. By this criterion two-thirds of the chemicals analyzed were mutagenic--; 11% with and 55% without metabolic activation. Of the 191 chemicals examined; 119 were polycyclic aromatic hydrocarbons; 25 were nitro or nitroso compounds, 9 were alkyl halides; 7 were purine or pyrimidine derivatives and the remaining 31 were from other chemical classes. We also defined mutagenic potency as the concentration of a compound that increases the mutant frequency by 10 times the spontaneous frequency. Mutagenic potencies of the compounds examined varied over a range of 5 X 10(6). We have also found large interlaboratory variations in the mutagenic potencies. Such variation in potency could be reduced by normalizing the results to a standard mutagen such as N-methyl-N'-nitro-N-nitrosoguanidine. The role of the V79 assay in mutagenicity and carcinogenicity testing is discussed and recommendations are suggested for future investigation.

Mutagenesis by chemical agents in V79 chinese hamster cells: a review and analysis of the literature. A report of the Gene-Tox Program

Results from tests on a total of 180 compounds in the Salmonella/microsome assay and its adapted procedures are summarized. The following specific problems were analyzed: the predictive value of the test; frequency distribution of chemicals (classes) according to their mutagenic activity; quantitative relationship between mutagenicity versus electrophilicity versus carcinogenicity of some selected carcinogens; chemicals that are activated into mutagens by human-liver enzymes; compounds that have been tested in the presence of rodent hepatic versus extra-hepatic tissue fractions; and some factors involved in the efficient detection of mutagens in vitro, i.e. the source and concentration of liver microsomal protein required for maximal mutagenic activity. As 34 chemicals have also been tested in microsome- or cell-mediated mutagenicity assays by using V79 Chinese hamster cells, an intercomparison is made of test results obtained in bacterial and mammalian assays.

Validation and comparative studies on 180 chemicals with S. typhimurium strains and V79 Chinese hamster cells in the presence of various metabolizing systems.

C.A.H. Bigger

Papers

Differences between products of binding of 7,12-dimethylbenz[a]anthracene to DNA in mouse skin and in a rat liver microsomal system